24 hours of hypothermic oxygenated perfusion mitigates transcriptomic remodeling in DCD and DBD hearts, supporting successful transplantation outcomes

Background To expand the donor pool for heart transplantation, donation after circulatory death (DCD) has been introduced alongside donation after brain death (DBD). Optimal preservation is crucial for maintaining donor organ viability. Hypothermic oxygenated perfusion (HOPE) has emerged as a promising heart preservation technique. Purpose This study aimed to identify transcriptional changes in DBD and DCD hearts from donation to post-transplantation, assessing the effects of 24-hour HOPE. Methods Hearts from 16 female pigs (DBD: n=8, DCD: n=8) were procured, preserved for 24 hours using HOPE, and transplanted into healthy recipients. Animals were terminated 2 hours after achieving stable circulation following weaning from cardiopulmonary bypass. Serial left ventricular biopsies were collected from the donor heart at baseline, post-donation, after 24 hours of preservation, early reperfusion, and at termination. Bulk RNA sequencing was performed, followed by differential gene expression and pathway enrichment analyses. Results Significant differences in gene expression were observed between DCD and DBD hearts post-donation, with 49 genes upregulated and 134 genes downregulated in DCD procured hearts compared to DBD hearts. Pathway analysis (KEGG and GSEA) revealed gene enrichment, particularly in inflammatory (IL17, TNFα, NF-kβ signalling, antigen processing and presentation) and cell death (regulation of intrinsic apoptotic signalling, programmed cell death) pathways in DBD hearts. Notably, during the 24 hours of HOPE preservation, no differentially expressed genes were detected between DCD and DBD hearts. Similarly, no significant differential expressed genes were observed after early reperfusion and at termination. These findings align with the functional outcomes, as both DBD and DCD hearts showed equal functionality and success after transplantation. Conclusion Our findings indicate that while DBD and DCD hearts exhibit distinct transcriptional differences prior to preservation, 24 hours of HOPE effectively preserves both at the functional and transcriptional levels. These findings suggest that HOPE could extend the viable preservation time of both DBD and DCD donor hearts, supporting its potential role in improving preservation strategies for heart transplantation.Volcano plots post-donation DCD vs DBD Pathways enrichment post-donation